Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets

Abstract

Remdesivir is an antiviral approved for COVID-19 treatment, but its wider use is limited by intravenous delivery. An orally bioavailable remdesivir analog may boost therapeutic benefit by facilitating early administration to non-hospitalized patients. This study characterizes the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. Both GS-621763 and GS-441524 inhibit SARS-CoV-2, including variants of concern (VOC) in cell culture and human airway epithelium organoids. Oral GS-621763 is efficiently converted to plasma metabolite GS-441524, and in lungs to the triphosphate metabolite identical to that generated by remdesivir, demonstrating a consistent mechanism of activity. Twice-daily oral administration of 10 mg/kg GS-621763 reduces SARS-CoV-2 burden to near-undetectable levels in ferrets. When dosed therapeutically against VOC P.1 gamma γ, oral GS-621763 blocks virus replication and prevents transmission to untreated contact animals. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection.

Very low levels of remdesivir resistance in SARS-COV-2 genomes after 18 months of massive usage during the COVID19 pandemic: A GISAID exploratory analysis

“…Nevertheless, earlier (outpatient) usage could restore clinical benefit, and research with oral remdesivir prodrugs continues (e.g. GS-441524 ( Cox et al, 2021 )).…”

Drug Combinations as a First Line of Defense against Coronaviruses and Other Emerging Viruses

“…While approved drugs have the advantage that FDA guidance on the development of drug combinations allows for more rapid development ( https://www.fda.gov/media/80100 ), drugs that have passed human safety trials should also be considered as information about them becomes available. In this respect, it will be important to follow the development of AT-527 ( 128 ), other potential oral SARS-CoV-2 polymerase inhibitors ( 97 , 129 ) including oral forms of RDV ( 139 – 141 , 200 ) as well as the oral protease inhibitor GC-376 ( 102 , 125 ). As new oral/inhaled drugs with the same targets but better efficacy and PK become available, they should be analyzed as substitutes in previously characterized drug synergies.…”

Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern

“…Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe disease and it prevents disease progression in outpatients ( Beigel et al, 2020 ; Gottlieb et al, 2021 ). While remdesivir requires intravenous administration, an oral prodrug of GS-441524 is being developed ( Cox et al, 2021 ). Molnupiravir (MK-4482 or EIDD-2801), a prodrug of the nucleoside analogue EIDD-1931 (β-D-N4-hydroxycytidine), is another inhibitor of the viral RdRp and was originally developed against different RNA viruses such as influenza ( Painter et al, 2021 ).…”